The spread of HIV infection is a major threat to public health worldwide and the development of an effective vaccine strategy is of the highest significance. Currently, the greatest and most pressing challenge to AIDS vaccine research is to develop a vaccine strategy that can induce strong and broadly neutralizing antibodies (bNAbs) against HIV. We have assembled a team of investigators who possess specialized expertise in antigen design, B cell analysis, virology, and vaccine immunology to develop an effective vaccine strategy to induce bNAbs against the conserved epitopes in the membrane-proximal external region (MPER) of the HIV envelope glycoprotein (Env), which are targets for several potent and broadly neutralizing monoclonal antibodies against HIV. This collaborative effort will explore strategies to overcome major obstacles that hinder the induction of bNAbs against the MPER of the HIV Env. Specifically, we will explore different vaccine strategies to present the MPER in its neutralization-competent structure and investigate alternative approaches to overcome the weak antigenicity of MPER for inducing strong bNAbs against HIV. Building on our recent success in eliciting MPER-specific HIV NAbs by a HA/gp41 chimeric antigen and employing multidisciplinary approaches, we will: 1) modify vaccine design and develop new chimeric protein antigens to selectively augment induction of bNAbs against the conserved epitopes in the HIV Env MPER; 2) determine the targets of vaccine-induced MPER-specific neutralizing antibodies and modify vaccine design to selectively augment induction of such antibodies; and 3) optimize the immunization regimens and investigate the use of adjuvant for inducing strong neutralizing antibodies against MPER of the HIV Env. The successful development of these vaccine strategies will be of great significance for HIV vaccine development, and knowledge gained through these studies could also be applied to vaccine design against other conserved neutralizing epitopes in the HIV Env, which are very likely to be conformational sensitive, cryptic, and weakly immunogenic like the epitopes in the MPER.